A phenethylamine

Figure 11.14 Analysis of amphetamines by GC-NPD following HS-SPME exti action from human hair (a) Normal hair (b) normal hair after addition of amphetamine (1.5 ng) and methamphetamine (16.1 ng) (c) hair of an amphetamine abuser. Peak identification is as follows 1, a-phenethylamine (internal standard) 2, amphetamine 3, methamphetamine 4, N-propyl-/3-phenethyamine (internal standard). Reprinted from Journal of Chronatography, B 707,1. Koide et ai, Determination of amphetamine and methamphetamine in human hair by headspace solid-phase microextraction and gas cliromatography with niti ogen-phosphoms detection, pp. 99 -104, copyright 1998, with permission from Elsevier Science.

Scheme 34 shows the synthesis of the bc portion (336), which possessed three of the nine asymmetric centers present in cobyric acid. Retrosynthesis determined that (336) could be obtained, via sulfide contraction, from the two intermediates (337) and (338). Ring c was synthesized from (+)-camphor quinone (not shown). Ring b (337) was obtained from 8-methyl-j8-acetylacrylic acid (339), the two adjacent chiral centers being generated in the required relative orientation by a Diels-Alder cycloaddition with butadiene in the presence of tin(IV) chloride. Fractional crystallization served to resolve the diastereomeric a-phenethylamine salts derived from them, eventually affording the compound (340). Oxidation with chromic acid cleaved the double bond in (340) and one of the newly generated... 

This is probably the most dramatic example of the loss of potency from an amphetamine (DOM, active at maybe 3 milligrams) to a phenethylamine (only one tenth as active). It is so often the case that the first of a series is not the most interesting nor the most potent member. As intriguing and as difficult-to-dellne as the 2C-D story might be, the next higher homologue of this set, 2C-E, is maximally active at the 15 to 20 milligram level, and is, without any question, a complete psychedelic. 

If a drug has been initially developed (and initially named) as an amphetamine derivative (three carbon chain) then the two-carbon chain analogue will use the original name (or a symbolic part of it) with the term 2C ahead of it. The two-carbon analogue of DOB (a three-carbon chain compound) will become 2C-B. DOI becomes 2C-I, DON becomes 2C-N, and DOET becomes 2C-E. Each of these is a substituted amphetamine derivative lacking one carbon atom, thus becoming a phenethylamine derivative. Most of these have 2,4,5-substitution patterns. 

Thus, 2-C implies that a known amphetamine drug has been shortened to a phenethylamine, and 3-C inplies that a known phenethylamine has been lengthened to an amphetamine. A great number of the former have been made and have proven to be most rewarding. Only a few of the latter are known, but most of them will eventually prove to be potent psychedelics. 

EXTENSIONS AND COMMENTARY This specific compound is probably the first sulfur-containing phenethylamine to have been evaluated as a potentially active CNS stimulant or psychedelic. It was a complete, total, absolute unknown. The first trials were made at the sub-microgram level, specifically at 0.25 micrograms, at 11 30 AM on September 3,1975. Part of this extreme precaution was due to the uniqueness of a new heteroatom in a phenethylamine system. But part was due to the strange manic excitement that occurred at the time of the isolation and characterizing of the final product in the laboratory. Although it was certainly all placebo response, I was jumpy and unable to stay in the lab for more than a few minutes at a time. Maybe dust in the air Maybe some skin contact with the free... 

A phenethylamine has a benzene ring as its centerpiece and it, too, has a floppy two-carbon chain extending out from it and also terminating in an amino group. In a reaction that is exactly analogous to that of the tryptamines, this amine can pick up a carbon atom and bend back to react... 

Alkaloid synthesis from yic-tricarbonyl compounds. Wasserman s group1 has used the strongly electrophilic character of the central carbonyl of a Wc-tricarbonyl system for synthesis of several alkaloids. Thus several isoquinoline alkaloids can be prepared by reaction of a phenethylamine with the tricarbonyl 1. 

In view of the selectivity of lithiation of the imine system, to get a -syn deprotonation and subsequently substitution, Fraser investigated the scope of asymmetric induction of a chiral imine, i.e. cyclohexenone imine, that derives from TV-a-phenethylamine 34. On alkylation by Mel or EtI, he obtained a-substituted cyclohexanones in ee of 50%66. Ma-Jacheet and Horeau67 and Yamada and coworkers68, who used this technique, obtained 25-45% ee. Free rotation around the C—N bond, as well as the lack of control of the configuration of the alkylation product, were the reasons ascribed for the low amount of asymmetric induction. A better enantioselectivity was achieved when the imine had an inner ligand (OMe), that makes the lithioenamine 35 more rigid by /w/ramolecular chelation. 

S)-l-Alkyl-l,2, 4-tetrahydroisoquinolines. The bis(trimethylsilyl) ether (2) of 1 has been used as a chiral auxiliary to effect alkylation of tetrahydroisoquinoline (equation 1) with high enantioselectivity. The chiral propanediol is much more effective than (R)-(— )-a-phenethylamine, and moreover leads consistently to (S)-l-alkyl derivatives. 

The Pictet-Spengler cyclization proceeds in vitro as in Fig. 2, which shows a hypothetical example in the isoquinoline series, via several distinct intermediates which cannot be isolated in the laboratory (6c, I Ob). Addition of acetaldehyde to a phenethylamine activated by a phenolic hydroxy group first affords a carbinolamine, which, under the influence of acid, dehydrates to a Schiff base that is most likely present as the more stable E isomer, affording on protonation directly the racemic tetrahydro-isoquinoline [( )-TIQ] (I0a,b). In attempting to explain the formation of optically active mammalian isoquinolines in vivo, we cannot disregard the possibility that the phenolic group of the phenethylamine substituent is... 

Shulgin, A. and Shulgin, A., Phenethylamines I Have Known and Loved, Transform Press, Berkeley, CA, 1991. 

Serotonin and norepinephrine reuptake inhibitors. The only member of this class which has received regulatory approval is venlafaxine (Effexor). Venlafaxine is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents. In a retrospective review of 35 consecutively treated overweight or obese outpatients with BED, venlafaxine 75-300 mg daily given for 1 to 43 weeks appeared to reduce the frequency of binge eating and to lower body weight (Malhotra et al. 2002). Reported side effects included dry mouth, sexual dysfunction, insomnia and nausea As there have thus far been no published randomised controlled trials, its place in the treatment of BED must remain uncertain. 

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